Despite improvements in breast cancer therapy in recent years, additional therapies need to be developed. New therapies may have activity by themselves or may have utility in combination with other agents. Population, preclinical, and basic data suggest the insulin-like growth factor (IGF) system functions to maintain the malignant phenotype in breast cancer. Since the IGFs act via transmembrane tyrosine kinase receptors, targeting of the key receptors could provide a new pathway in breast cancer. In addition, IGF action enhances cell survival, so combination of anti-IGF therapy with conventional cytotoxic drugs could lead to synergistic effects. In this review, we will discuss the rationale for targeting the IGF system, potential methods to disrupt IGF signaling, and identify potential interactions between IGF inhibitors and other anti-tumor strategies. We will also identify important issues to consider when designing clinical trials.